Submissions for variant NM_000038.6(APC):c.6487A>C (p.Lys2163Gln)

gnomAD frequency: 0.00002  dbSNP: rs759728732

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775341	SCV000909613	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779713	SCV000916468	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: APC c.6487A>C (p.Lys2163Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249906 control chromosomes, predominantly at a frequency of 0.00033 within the East Asian subpopulation in the gnomAD database. This frequency is about 5 fold higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.4e-05 vs 7.1e-05), suggesting this variant is possibly a benign polymorphism primarily found in East Asians. c.6487A>C has been reported in the literature in in a Korean gastric cancer patient with co-occurrence of somatic APC variant c.1273delG, and authors classified variant of interest as benign (Kim_2017). However, this report does not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign, n=1; VUS. n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535529	SCV001217969	uncertain significance	Familial adenomatous polyposis 1	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2163 of the APC protein (p.Lys2163Gln). This variant is present in population databases (rs759728732, gnomAD 0.03%). This missense change has been observed in individual(s) with gastric cancer (PMID: 29050249). This variant is also known as p.K2145Q. ClinVar contains an entry for this variant (Variation ID: 630197). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284248	SCV001469927	uncertain significance	not provided	2020-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775341	SCV002658124	benign	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003983202	SCV004800533	likely benign	APC-related disorder	2024-01-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).